Pathogenesis of Diabetic Retinopathy .pptx

This PPT is about pathogenesis & ocular complications related to diabetes

1. Who is at risk of developing DR ? Mechanism of vision loss in Diabetes. Presented by:- Ranjita Amanatya 2 nd year PG VIMSAR, BURLA

2. Who is at risk of developing DR? A B C D E Non-Modifiable Risk Factors Age > 45 years old Family History of T2D (first degree relative) Ethnicity (i.e. African American, Hispanic-American, Asian American, Pacific Islander) Genetics ( Susceptibility Loci ) History of gestational diabetes or of a baby weighing more than nine pounds

3. Who is at risk of developing DR? Modifiable Risk Factors • Body Mass Index ≥ 25 kg/m2 • Hypertension • Dyslipidemia (low HDL cholesterol, high triglycerides) • Cardiovascular Disease • Impaired fasting glucose (≥100mg/dL) • Impaired glucose tolerance 2 hr plasma glucose ≥140 mg/dL) • HbA1c > 5.7%

4. Who is at risk of developing DR? Vitamin Deficiencies o Vitamin K o Vitamin D Gut bacteria that cause increased: Nutrient absorption Cellular uptake of triglycerides Lipogenesis Chronic low-grade inflammation Capacity to extract energy from the diet Modifiable Risk Factors Lifestyle o Sedentary lifestyle o Physical inactivity o Alcohol consumption o Smoking o Low fiber diet o Food with a high glycemic index o Consumption of saturated fats o Sweet drinks o Obstructive Sleep Apnea

5. Global gender specific prevalence of diabetes by age. y-axis is percent of population having diabetes mellitus. x-axis depicts intervals of age. Global estimates of number of persons with diabetes mellitus in 2000 compared with projected numbers for the year 2030 in three age groups Estimated numbers of people with diabetes mellitus in selected countries projections for 2030

6. Systemic and Ocular Factors Influencing Diabetic Retinopathy Systemic Factors Glycemic Control Type1DiabetesMellitus Type 2 Diabetes Mellitus Rapidity of Improvement in Glycemic Control Glycemic Variability Insulin Use in Type 2 Diabetes Pancreas and Pancreas–Renal Transplantation Blood Pressure Serum Lipids Anemia Nephropathy Pregnancy Other Systemic Factors Effects of Systemic Drugs Diuretics Renin–Angiotensin System Drugs Aldose Reductase Inhibitors Drugs That Target Platelets Statins Protein Kinase C Inhibitors Thiazolidinediones ( Glitazones ) Miscellaneous Drugs Ocular variables a/w increasing severity of DR:- smaller retinal arteriole/venule ratio, presence of retinal A/V nicking, focal arteriolar narrowing.

7. Posterior Segment Complications Visual distortion, “blurred vision” or “floaters” are signs of development of irreversible blindness if left untreated. Vision loss d/t retinal problems (tractional or rhegmatogenous retinal detachment) become permanent and even irreparable in short period of time (days to months). Color vision changes and contrast sensitivity loss noted with early DR. Chance of vision loss, be it moderate vision loss in the case of diabetic macular edema (DME) or severe vision loss in proliferative diabetic retinopathy (PDR).DME leads to moderate vision loss in slower time frame. Highly- threatening retinopathy (PDR) leads to SVL, often acutely and can present with advanced disease. Nonproliferative diabetic retinopathy (NPDR) with associated hard exudates, microaneurysms , and intraretinal hemorrhages. Proliferative diabetic retinopathy (PDR) with fibrovascular proliferation on the surface of the retina extending from the optic nerve along the arcade vessels causing traction on the macula

8. REVERSIBLE AND NON-REVERSIBLE CAUSES OF VISION LOSS IN DIABETIC RETINOPATHY Reversible causes of vision loss :- DME, Non-clearing vitreous hemorrhage (NCVH), Vitreomacular traction (VMT) Epiretinal membrane (ERM) Tractional retinal detachment (TRD) without macular detachment. Non-reversible causes of vision loss :- Chronic DME, DME complicated by subfoveal HE or fibrosis, Advanced TRD with the detachment of the macula, TRD complicated by RRD, Macular ischemia, NVG.

9. Glucose Transport in the Retina Glucose is transported in retina mainly through GLUT1 transporter. GLUT1 is expressed in tissues with blood barrier properties , such as blood-brain barrier (BBB) and blood-ocular barriers. GLUT1 is only glucose transporter present in retinal endothelial cells . Glucose enters cytoplasm of endothelial cells of inner BRB by transport across endothelial lumenal membrane via GLUT1. GLUT1 is expressed in a variety of tissues, such as capillary endothelial cells, retinal pigmented epithelium, ciliary body, endothelium of canal of Schlemm and capillaries and pigmented epithelium of iris. Alterations on absolute amount and/or subcellular distribution of GLUT1 in retinal endothelial cells are likely to be of critical importance in development of diabetic retinopathy. GLUT1 is upregulated in membranes from retinal microvessels of diabetic patients. GLUT2 and GLUT3 , are also present in retina , mainly at level of Muller and neuronal cells , respectively.

10. A B C D Four hypotheses have previously been advanced to explain mechanism of hyperglycemia-induced microvascular damage Increased polyol pathway flux Advanced glycation end products (AGEs) Activation of protein kinase C (PKC) Increased hexosamine pathway flux.

11. Increased Polyol Pathway Flux “Polyol pathway” refers to enzymatic reduction of glucose to acyclic polyol , such as sorbitol, which in some cases is reoxidized to another carbohydrate, such as fructose. Aldose reductase ( AR), first enzyme in polyol pathway. Hyperglycemiainduced superoxide (O2 ) production inhibits GAPDH,causing an accumulation of upstream metabolites. These are diverted into the four alternative metabolic pathways, each of which leads to vascular and interstitial tissue damage

12. Advanced Glycation End Products (AGEs) AGE formation alters properties of several extracellular matrix proteins. AGEs originate from number of pathways:- Auto-oxidation of glucose to glyoxal, Decomposition of Amadori product to 3-deoxyglucosone Fragmentation of glyceraldehyde-3-phosphate and dihydroxyacetone phosphate to methylglyoxal. C ell-associated-binding proteins for AGEs:- OST-48, 80K-H, galec tin-3, macrophage scavenger receptor type II, RAGE.

13. Hyperglycemia leads to the intraocular production of advanced glycation end product (AGE) precursors. These lead to modification matrix proteins and integrins and promote the synthesis of growth factors and cytokines including VEGF

14. Activation of Protein Kinase C (PKC) Protein kinase C is a family of at least 11 isoforms, 9 of which are activated by lipid second messenger diacylglycerol (DAG). Intracellular hyperglycemia increases DAG in both the retina and renal glomeruli by increasing synthesis from dihydroxyacetone phosphate.Inturn , activates PKC in vascular cells, retina, and glomeruli. Hyperglycemia also activates PKC isoforms indirectly through ligation of AGE receptors and via increased activity of polyol pathway. Hyperglycemiainduced superoxide production prevents the normal conversion of glyceraldehyde-3-P into 1,3 diphosphoglycerate . This diverts upstream metabolites into the polyol, hexosamine , and AGEpathways . Excess glyceraldehyde-3-P is converted into diacylglycerol (DAG), which subsequently activates protein kinase C (PKC)

15. Increased Hexosamine Pathway Flux Changes in gene activation, lead to vascular endothelial dysfunction and other changes consistent with those seen in diabetic retinopathy. PKC isoforms are activated by glucosamine without membrane translocation. The hexosamine pathway produces glucosamine-6-P by diverting excess fructose-6-P from glycolysis. This leads to the synthesis of glycolipids, glycoproteins, proteoglycans, and TGF-b

16. Hemodynamics, Macular Edema and Starling’s Law Movement into & out of body’s capillaries,including those of retina,is dependent on hydrostatic and oncotic pressures. The four primary Starling’s forces are as follows:- Hydrostaticpressurewithinthecapillarylumen (Pc) Hydrostatic pressure within the retinal intersti tium (Pi) Capillary oncotic pressure (Qc) Interstitial oncotic pressure (Qi) Edema:- Abnormal swelling of soft tissues – The retinal interstitium . Can be cytotoxic ,where fluid accumulates within interstitial spaces, occurs with severe ischemia , such as following central retinal artery occlusions. Starling’s law applies to vasogenic edema , most common form of edema in retinal vasculopathies such as diabetic macular edema and retinal vein occlusions. Retinal edema occurs when net hydrostatic force (forcing fluid into interstitium ) exceeds net oncotic force (drawing fluid into the capillary lumen) across capillary walls.

17. Histological studies Swelling and degeneration of Muller, bipolar, ganglion and photoreceptor cells, and extracellular cystic spaces Retinal thickening appears to correlate with blood retinal barrier breakdown. Cause of retinal thickening was extracellular expansion.Ischemia lead to small amount of intracellular swelling, major contribution to macular edema is extracellular fluid accumulation. Once retinopathy is established, retinal blood flow increases. vitreous fluorophotometry has shows BRB,represents early gap junction protein loss allowing molecules smaller than albumin to pass out of the capillary lumen. Retinal pigment epitheliopathy, first manifestation of diabetic retinopathy. Cystoid macular edema develops in two retinal layers:- I nner nuclear layer and outer plexi form layer. patient with type II DM showing mild parafoveal macular edema and microaneurysms .

18. Development of Proliferative Diabetic Retinopathy VEGF molecules fit into a broad group of compounds, which can be divided into several families– A,B,C,D,E,andplacental-derivedgrowthfactor (PDGF). VEGF molecules stimulate known signaling pathways, including protein kinase C, in endothelial cells. There are at least four tyrosine kinase VEGF receptors: VEGFR-1, VEGFR-2, VEGFR-3, and neuropilin . VEGFR-1 is pivotal in neovascularization. VEGF is capable of stimulating angiogenesis (through sprouting, intussusceptions, andrecruitment of pro genitor cells), increasing vascular permeability and vasodilation, preventing endothelial apoptosis, and recruiting inflammatory cells . hyperglycemiadriven production of electron donors (FADH2 and NADH)creates a proton gradient across the mitochondrial membrane, inhibiting electron transport at complexIII.This prolongs the half-life of coenzyme Q, thereby leading to the production of superoxide (O2 )

19. Perturbations in neuroglia homeostasis lead to the release of several vasopermeability (VEGF, histamine, and TGF-b) and probarrier factors, which affect the integrity of capillary tight junctions and endothelial membrane integrity Extracellular vascular endothelial growth factor A (VEGF-A) binds to a transmembrane receptor molecule (VEGFR, a tyrosine kinase) resulting in gene expression and protein synthesis. This leads to cell migration and survival. Through the activation of nitric oxide synthetase and prostaglandin synthesis, vascular tone and permeability are affected and angiogenesis may occur

20. Diabetic Papillopathy An uncommon, hyperemic optic disk swelling that occurs in patients with long-standing diabetes. Prevalence is 1.4% in diabetic patients and presents bilaterally in 50% of cases. Characterized by optic disk swelling resulting from vascular leakage and axonal edema in the area surrounding the optic nerve head, present with intra-retinal hemorrhages and exudates. Associated with small cup/disc ratio and rapid glycemic/metabolic control. self-limited and has a good visual prognosis. disc swelling often resolves spontaneously within 3–4 months

21. Neovascularization in Diabetic Retinopathy Ischemia and Neovascularization in Diabetic Retinopathy Growth Factors Basic Fibroblast Growth Factor ( bFGF ) Insulin-Like Growth Factors (IGF) Platelet-Derived Growth Factor (PDGF) Vascular Endothelial Growth Factor (VEGF)

22. Genetic Factors Aldose Reductase Gene VEGF Gene RAGE Gene Angiotensin-Converting Enzyme Gene PAI-1 Gene Endothelin Genes Nitric Oxide Synthase Genes

23. Anterior Segment Complications The swings from hypoglycemia to hyperglycemia in diabetic patients can cause transient refractive changes. Both myopic and hyperopic shifts are possible following several days or weeks of hyperglycemia. The refractive changes are thought to arise from alterations in the shape and thickness of the lens secondary to osmotic gradients created by abnormal blood glucose levels. Develop presbyopia at an earlier age as compared to age-matched non-diabetics. Lens and zonule changes, loss of ciliary muscle tone, and a deficit in neural input to the ciliary muscle are thought to contribute to this early loss of accommodation. Refractive Changes

24. Anterior Segment Complications Cataracts 2-5 times more frequently in patients with diabetes. Risk can increase to 15-25 times in diabetic patients less than 40 years.Most common cause of visual impairment among older onset diabetic patients. Posterior subcapsular and cortical cataracts. Increased osmotic stress from activation of the polyol sorbitol-aldolase reductase pathway, increased oxidative stress, and non-enzymatic glycation of lens proteins. Posterior capsular cataract focal cortical cataract

25. Diabetes and Glaucoma Risk diabetic patients are at significantly increased risk of developing POAG. DM increases apoptosis induced by glaucoma independent of IOP. Loss of vascular autoregulation seen in DM may exacerbate hypoperfusion induced by increased IOP. NVG, ischemia to the retina and posterior segment leads to increased levels of angiogenic growth factors, such as vascular endothelial growth factor (VEGF), in the eye. P resence of angle neovascularization typically precedes rise in intraocular pressure. diabetes is among most common factors for NVG. NVG is seen in patients who have coexisting proliferative diabetic retinopathy (PDR) Neovascularization of the iris secondary to proliferative diabetic disease

26. Diabetes and the Cornea 1)Increase in Epithelial Thickness:- An increase in central corneal epithelial thickness. 2)Abnormal Basement Membrane Formation Accumulation of AGEs on BM and proteolytic degradation of BM components due to upregulation of MMPs are plausible causative culprits for pathogenesis of corneal epithelial/Bowman’s layer keratopathy. 3)Impaired Epithelial Barrier Function Accumulation of AGEs on the epithelial BM alters the epithelial cell behavior, leading to a subsequent weakening of the epithelial barrier function in the diabetic cornea. Impaired corneal epithelial barrier function predisposes diabetic patients to corneal infections, such as infectious keratitis. 4)Increased Epithelial Fragility Loosened epithelial adhesion and fragility is due to thickened BM,decreased penetration of anchoring fibrils into stroma and enhanced MMP activity in elevated glucose states. 5)Poor Healing Capacity of Epithelial Defects corneal healing in diabetic state is slowed by combination of delays in migration of epithelial cells and inhibitions in cell attachment with BM components.

27. CORNEAL ENDOTHELIUM Morphological Abnormalities Structural changes in corneal endothelial cells secondary to the chronic metabolic stress. Functional Abnormalities Leading to Increased Water Content in the Atroma and Folds in Descement’s Membrane Hyperglycemia causes abnormal corneal hydration control and eventual stromal swelling. Elevated glucose level reduce activity of Na+/K+ ATPase enzyme, which is a major component of corneal endothelial fluid pump. Inhibition of this endothelial pump causes increased water content in stromal layer and eventually, increased corneal thickness. Cornea can only swell in posterior direction, presence of small folds in Descemet’s membrane.

28. CORNEAL NERVES Reduced Corneal Sensation Mechanisms that play a role in nerve damage include hyperglycemia-induced inflammation and oxidative stress and altered metabolic and signaling pathways. Reductions in total nerve fiber and density have been related to the loss of both somatic and corneal sensations. With diminished sensation, the cornea is more vulnerable to trauma, erosion, and ulceration.

29. Dry Eye Syndrome (DES) ( 54.3%) 50% more common among women than men. has a positive correlation with the level of glycated hemoglobin. 20% of dry eye syndrome may occur in individuals with Type 2 diabetes aged between 43 and 86 years. Sustained hyperglycemia triggers an inflammatory cascade leading to corneal epithelial dysfunction, lacrimal gland dysfunction, decreased mucin production, and diabetic keratopathy, lead to decreased tear formation and tear film instability causing the dry eye syndrome. symptoms include foreign body sensation, burning, itching, excessive tearing, discharge, redness, light-sensitivity, and intermittent blurring of vision.

30. 01 02 DIABETES AND NEURO-OPHTHALMOLOGIC COMPLICATIONS Cranial Nerve Palsies in Diabetes DR affecting cranial nerves innervating eye muscles leading to symptomatic ocular misalignment and thus binocular diplopia. Nerves are damaged by microvascular injury of small blood vessels that supply nerves, a common serious complication of diabetes. The excess glucose causes abnormal thickening and weakening of the blood vessel basement membranes, leading to bleeding and slowing of blood flow. This poor blood flow to nerves and neurons causes neuronal ischemia, leading to loss of function. Diabetes most commonly affects the third cranial nerve (III) followed by the sixth cranial nerve (VI), which control eye muscles affecting ocular movements.Isolated palsies of CN III and CN VI secondary to diabetes occur significantly more frequently than palsies of multiple nerves at the same time. Pupils in Diabetes Pupils may also be affected in patients with diabetes, specifically leading to diminished accommodative amplitude. Accommodation relies on integration from sensory, neuromuscular, and other biophysical input to change the lens of the eye in order to automatically adjust the eye’s focus on objects at near and far distances. left partial pupil-sparing CN III palsy

31. 01 02 03 04 Diabetes and Ocular Infections RHINO-ORBITAL-CEREBRAL MUCORMYCOSIS PRE-SEPTAL & ORBITAL CELLULITIS INFECTIOUS KERATITIS ENDOPHTHALMITIS corneal infiltrate and pannus

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